EP0657164A1 - Staurosporinderivate enthaltende Arzneimittel - Google Patents

Staurosporinderivate enthaltende Arzneimittel Download PDF

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Publication number
EP0657164A1
EP0657164A1 EP94308954A EP94308954A EP0657164A1 EP 0657164 A1 EP0657164 A1 EP 0657164A1 EP 94308954 A EP94308954 A EP 94308954A EP 94308954 A EP94308954 A EP 94308954A EP 0657164 A1 EP0657164 A1 EP 0657164A1
Authority
EP
European Patent Office
Prior art keywords
active ingredient
composition according
staurosporine
composition
glyceride
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
EP94308954A
Other languages
English (en)
French (fr)
Other versions
EP0657164B1 (de
Inventor
Roy Lindsay Allen Henry
Graham Paul Matthews
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Novartis Pharma GmbH
Novartis AG
Original Assignee
Novartis Erfindungen Verwaltungs GmbH
Ciba Geigy AG
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Novartis Erfindungen Verwaltungs GmbH, Ciba Geigy AG filed Critical Novartis Erfindungen Verwaltungs GmbH
Publication of EP0657164A1 publication Critical patent/EP0657164A1/de
Application granted granted Critical
Publication of EP0657164B1 publication Critical patent/EP0657164B1/de
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4858—Organic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • This invention relates to pharmaceutical compositions, particularly pharmaceutical compositions comprising a staurosporine as active ingredient.
  • US Patent 5 093 330 describes staurosporine and N-substituted derivatives thereof as pharmaceuticals for use in tumour inhibition and inflammation inhibition, for antibacterial use and for use in combating arteriosclerosis, diseases of the cardiovascular system and of the central nervous system.
  • staurosporines have low solubility in water.
  • N-benzoylstaurosporine an especially preferred compound, has a solubility of less than 01.mg/litre.
  • the staurosporines have been found to have low or negligible bioavailability.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a solution or dispersion of a staurosporine active ingredient in a saturated polyalkylene glycol glyceride.
  • the staurosporine active ingredient may be any of those described in US Patent No. 5093330.
  • Preferred compounds are N-acylstaurosporines including N-benzoylstaurosporine, N-(3-nitrobenzoyl)staurosporine, N-(3-fluorobenzoyl)staurosporine, N-trifluoracetylstaurosporine, N-phenylcarbamoylstaurosporine, N-(3-carboxypropionyl)staurosporine, N-methylaminothiocarbonylstaurosporine, N-tert-butoxycarbonylstaurosporine, N-(4-carboxybenzoyl)staurosporine, N-(3,5-dinitrobenzoyl)staurosporine, N-(2-aminoacetyl)staurosporine, N-alanylstaurosporine and their pharmaceutically acceptable salts.
  • An especially preferred active ingredient is N-
  • the saturated polyalkylene glycol glyceride may be, for example, a mixture of glyceryl and polyethylene glycol esters of one or more long chain saturated fatty acids, usually C8-C18 saturated fatty acids.
  • the acid component of such esters may be, for example, caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid or a mixture of two or more thereof.
  • the polyethylene glycol component of such esters generally has a molecular weight of 200 to 2000, preferably 1000 to 1800, especially 1400 to 1600.
  • the glycerides, i.e. the glycol-modified glycerides are usually mixtures of mono, di and triglycerides and polyethylene glycol mono and diesters.
  • Preferred polyalkylene glycol glycerides are those having a high Hydrophilic-Lipophilic Balance (HLB) value. Further preferred are glycerides which are mixtures of esters of one or more C8-C18 saturated fatty acids with glycerol and a polyethylene glycol having a molecular weight of 1000 to 2000, preferably 1200 to 1800, especially 1400 to 1600.
  • HLB Hydrophilic-Lipophilic Balance
  • An especially preferred material is available commercially from Gattefossé as Gelucire 44/14; this is a mixture of esters of C8-C18 saturated fatty acids with glycerol and a polyethylene glycol having a molecular weight of about 1500, the specifications for the composition of the fatty acid component being, by weight, 4-10% caprylic acid, 3-9% capric acid, 40-50% lauric acid, 14-24% myristic acid, 4-14% palmitic acid and 5-15% stearic acid.
  • the saturated polyalkylene glycol glycerides are either commercially available or may be prepared by known procedures. For example they may be obtained by partial alcoholysis of hydrogenated vegetable oils using the polyalkylene glycol, or by esterification of the saturated fatty acid, or mixture of such acids, using glycerol and the polyalkylene glycol.
  • the staurosporine active ingredient is generally present in an amount from 1 to 30%, preferably 5 to 25%, especially 10 to 20%, by weight of the composition.
  • compositions of the invention may also contain carriers or adjuncts such as those described in US Patent No. 5 093 330 or other conventional excipients.
  • the composition may be contained in capsules, usually hard capsules of gelatin or soft capsules of gelatin mixed with a plasticiser such as glycerol or sorbitol, or may be used as a dispersion in an aqueous medium, such as water, saline solution or a mixture of water with another, water-miscible, pharmaceutically acceptable solvent, for example in an amount of 0.5 to 70, preferably 5 to 50% by weight, optionally together with a preservative, for example a conventional preservative such as a benzoate, particularly an ester of p-hydroxybenzoic acid such as the methyl, ethyl, n-propyl, n-butyl or benzyl ester thereof or the sodium salt of the ester and other excipients such as dispersing agents and suspending agents.
  • a preservative for example a
  • the present invention also provides a method of preparing a pharmaceutical composition as hereinbefore described which comprises melting a saturated polyalkylene glycol glyceride, mixing a staurosporine active ingredient with the molten glyceride and allowing the resulting mixture to solidify.
  • the glyceride is conveniently melted by heating to a temperature 10 to 20°C above its melting point before addition of the staurosporine active ingredient as a powder.
  • Optional excipients may be added to the molten mixture.
  • the liquid mixture of the staurosporine active ingredient and glyceride may be poured into hard capsules or injected into soft capsules and allowed to solidify therein.
  • the solid solution or solid dispersion obtained on cooling the liquid mixture of the staurosporine active ingredient and glyceride may be remelted for introduction into capsules.
  • the capsules may contain, for example, from 1mg to 250mg of the staurosporine active ingredient.
  • composition of the invention When a composition of the invention is to be administered as a dispersion in an aqueous medium, e.g. water, a saline solution or mixture of water with a water-miscible pharmaceutically acceptable solvent, the solid solution or solid dispersion obtained on cooling the liquid mixture is conveniently broken up and dispersed in the aqueous medium by stirring or by ultrasonication.
  • an aqueous medium e.g. water, a saline solution or mixture of water with a water-miscible pharmaceutically acceptable solvent
  • compositions of the invention may be used in the treatment of the indications hereinbefore described.
  • the compositions may be administered in prophylactically or curatively effective amounts.
  • compositions containing daily doses of 1 to 1000mg of the active ingredient may be administered to warm-blooded animals having a body weight of about 70kg.
  • the compositions are particularly useful in the treatment of cancer.
  • Gelucire 44/14 (82 parts) is melted by heating to 60°C. Powdered N-benzoylstaurosporine (18 parts) is added to the molten material. The resulting mixture is homogenised and the dispersion obtained is introduced into hard gelatin capsules of different size, so that some contain a 25mg dosage and others a 75mg dosage of the staurosporine. The resulting capsules are suitable for oral administration.
  • Gelucire 44/14 (86 parts) is melted by heating to 60°C. Powdered N-benzoylstaurosporine (14 parts) is added to the molten material. The mixture is homogenised and the dispersion obtained is introduced into hard gelatin capsules of different size, so that some contain a 25mg dosage and others a 75mg dosage of the staurosporine. The resulting capsules are suitable for oral administration.

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  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Medicinal Preparation (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Compositions Of Macromolecular Compounds (AREA)
EP94308954A 1993-12-11 1994-12-02 Staurosporinderivate und Polyalkylenglykol-Glyceride enthaltende Arzneimittel Expired - Lifetime EP0657164B1 (de)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB939325395A GB9325395D0 (en) 1993-12-11 1993-12-11 Compositions
GB9325395 1993-12-11

Publications (2)

Publication Number Publication Date
EP0657164A1 true EP0657164A1 (de) 1995-06-14
EP0657164B1 EP0657164B1 (de) 1999-10-27

Family

ID=10746475

Family Applications (1)

Application Number Title Priority Date Filing Date
EP94308954A Expired - Lifetime EP0657164B1 (de) 1993-12-11 1994-12-02 Staurosporinderivate und Polyalkylenglykol-Glyceride enthaltende Arzneimittel

Country Status (17)

Country Link
US (1) US5736542A (de)
EP (1) EP0657164B1 (de)
JP (1) JPH07196512A (de)
KR (1) KR100366176B1 (de)
AT (1) ATE185970T1 (de)
AU (1) AU692801B2 (de)
CA (1) CA2137764C (de)
DE (1) DE69421366T2 (de)
DK (1) DK0657164T3 (de)
ES (1) ES2140512T3 (de)
GB (1) GB9325395D0 (de)
GR (1) GR3032368T3 (de)
IL (1) IL111872A (de)
NZ (1) NZ270109A (de)
PH (1) PH31454A (de)
PT (1) PT657164E (de)
ZA (1) ZA949824B (de)

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000048571A1 (en) * 1999-02-16 2000-08-24 Novartis Ag Spontaneously dispersible n-benzoyl staurosporine compositions
WO2000062781A1 (de) * 1999-04-20 2000-10-26 Florian Lang Arzneimittel enthaltend hemmstoffe der zellvolumenregulierten humanen kinase h-sgk
EP1102758A1 (de) * 1998-08-06 2001-05-30 Cephalon, Inc. Partikelformende zubereitungen welche kondensierte pyrrolocarbazole enhalten
WO2002017893A2 (de) * 2000-08-28 2002-03-07 Florian Lang Sgk2 und sgk3 als diagnostische und therapeutische targets
WO2004079003A1 (de) * 2003-03-03 2004-09-16 Florian Lang Sgk1 als diagnostisches und therapeutisches target
WO2004108132A1 (en) * 2003-06-06 2004-12-16 Novartis Ag Staurosporine derivatives for hypereosinophilic syndrome
WO2006082448A1 (en) * 2005-02-07 2006-08-10 Topotarget Uk Limited Assays for agents with selective cytotoxicty to hdac resistant cell lines
US7795246B2 (en) 1998-08-06 2010-09-14 Cephalon, Inc. Particle-forming compositions containing fused pyrrolocarbazoles
EP2305265A1 (de) 2003-08-08 2011-04-06 Novartis AG Kombinationen mit Staurosporinen

Families Citing this family (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6242473B1 (en) * 1999-01-08 2001-06-05 Maxim Pharmaceuticals, Inc. Treatment and prevention of reactive oxygen metabolite-mediated cellular damage
EP1201668A4 (de) 1999-07-13 2003-05-21 Kyowa Hakko Kogyo Kk Staurosporin-derivate
DK1372611T3 (da) * 2001-03-26 2006-09-18 Novartis Ag Farmaceutisk sammensætning omfattende staurosporin med ringe vandoplöselighed, et overfladeaktivt stof og en vandoplöselig polymer
KR101152470B1 (ko) 2003-08-13 2012-06-01 바이오콘 리미티드 치료제용 마이크로-입자 지방산 염 고형 투약 제형
US9994585B2 (en) * 2007-12-31 2018-06-12 Aphios Corporation Transplantation therapies
US20100168219A1 (en) * 2008-12-31 2010-07-01 Jonathan Steven Alexander Chronic inflammation and transplantation
US9034347B2 (en) 2011-12-19 2015-05-19 Arphios Corporation Drug delivery system and method for the treatment of neuro-degenerative disease
WO2014085494A1 (en) 2012-11-28 2014-06-05 Aphios Corporation Combination therapeutics and methods for the treatment of neurodegenerative and other diseases

Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS60185719A (ja) * 1984-03-06 1985-09-21 Ajinomoto Co Inc 抗腫瘍剤
EP0296110A2 (de) * 1987-06-15 1988-12-21 Ciba-Geigy Ag An Methylamino-Stickstoff substituierte Derivate von Staurosporin
JPH01143877A (ja) * 1987-11-30 1989-06-06 Asahi Chem Ind Co Ltd スタウロスポリン誘導体
WO1989007105A1 (en) * 1988-02-04 1989-08-10 Kyowa Hakko Kogyo Co., Ltd. Staurosporin derivatives
JPH029819A (ja) * 1986-11-06 1990-01-12 Asahi Chem Ind Co Ltd 抗血管レン縮剤および血管弛緩剤
EP0457295A2 (de) * 1990-05-16 1991-11-21 The Rockefeller University Verwendung eines Modulators der Proteinphosphorylierung zur Behandlung der Amyloidosis in Zusammenhang mit der Alzheimerschen Krankheit
WO1992017181A1 (en) * 1991-03-29 1992-10-15 The United States Of America, Represented By The Secretary, United States Department Of Commerce Pharmaceutical compositions and methods for preventing skin tumor formation and causing regression of existing tumors
WO1993007153A1 (en) * 1991-10-10 1993-04-15 Schering Corporation 4'-(n-substituted-n-oxide)staurosporine derivatives
JPH0597708A (ja) * 1991-10-02 1993-04-20 Lion Corp 歯周病治療剤
JPH05247055A (ja) * 1992-03-03 1993-09-24 Meiji Seika Kaisha Ltd スタウロスポリン誘導体及びそれを含有する抗腫瘍効果増強剤

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5093330A (en) * 1987-06-15 1992-03-03 Ciba-Geigy Corporation Staurosporine derivatives substituted at methylamino nitrogen

Patent Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS60185719A (ja) * 1984-03-06 1985-09-21 Ajinomoto Co Inc 抗腫瘍剤
JPH029819A (ja) * 1986-11-06 1990-01-12 Asahi Chem Ind Co Ltd 抗血管レン縮剤および血管弛緩剤
EP0296110A2 (de) * 1987-06-15 1988-12-21 Ciba-Geigy Ag An Methylamino-Stickstoff substituierte Derivate von Staurosporin
JPH01143877A (ja) * 1987-11-30 1989-06-06 Asahi Chem Ind Co Ltd スタウロスポリン誘導体
WO1989007105A1 (en) * 1988-02-04 1989-08-10 Kyowa Hakko Kogyo Co., Ltd. Staurosporin derivatives
EP0457295A2 (de) * 1990-05-16 1991-11-21 The Rockefeller University Verwendung eines Modulators der Proteinphosphorylierung zur Behandlung der Amyloidosis in Zusammenhang mit der Alzheimerschen Krankheit
WO1992017181A1 (en) * 1991-03-29 1992-10-15 The United States Of America, Represented By The Secretary, United States Department Of Commerce Pharmaceutical compositions and methods for preventing skin tumor formation and causing regression of existing tumors
JPH0597708A (ja) * 1991-10-02 1993-04-20 Lion Corp 歯周病治療剤
WO1993007153A1 (en) * 1991-10-10 1993-04-15 Schering Corporation 4'-(n-substituted-n-oxide)staurosporine derivatives
JPH05247055A (ja) * 1992-03-03 1993-09-24 Meiji Seika Kaisha Ltd スタウロスポリン誘導体及びそれを含有する抗腫瘍効果増強剤

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, vol. 112, no. 1, 1 January 1990, Columbus, Ohio, US; abstract no. 7781 *
CHEMICAL ABSTRACTS, vol. 112, no. 9, 26 February 1990, Columbus, Ohio, US; abstract no. 77240 *
CHEMICAL ABSTRACTS, vol. 119, no. 5, 2 August 1993, Columbus, Ohio, US; abstract no. 40959 *
CHEMICAL ABSTRACTS, vol. 120, no. 21, 23 May 1994, Columbus, Ohio, US; abstract no. 270948 *
DATABASE WPI Week 9008, Derwent World Patents Index; AN 90-055512 (08) *
PATENT ABSTRACTS OF JAPAN vol. 010, no. 031 (C - 327) 6 February 1986 (1986-02-06) *

Cited By (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1102758A4 (de) * 1998-08-06 2002-07-24 Cephalon Inc Partikelformende zubereitungen welche kondensierte pyrrolocarbazole enhalten
US7795246B2 (en) 1998-08-06 2010-09-14 Cephalon, Inc. Particle-forming compositions containing fused pyrrolocarbazoles
EP1102758A1 (de) * 1998-08-06 2001-05-30 Cephalon, Inc. Partikelformende zubereitungen welche kondensierte pyrrolocarbazole enhalten
US6660729B1 (en) 1998-08-06 2003-12-09 Cephalon, Inc. Particle-forming compositions containing fused pyrrolocarbazoles
KR100880859B1 (ko) * 1999-02-16 2009-01-30 노파르티스 아게 자발분산성 ｎ-벤조일-스타우로스포린 조성물
CN100367930C (zh) * 1999-02-16 2008-02-13 诺瓦提斯公司 可自发分散的n-苯甲酰基-星形孢菌素组合物
AU765776B2 (en) * 1999-02-16 2003-10-02 Novartis Ag Spontaneously dispersible N-benzoyl staurosporine compositions
US8722664B2 (en) 1999-02-16 2014-05-13 Novartis Ag Spontaneously dispersible N-benzoyl staurosporine compositions
US8575147B2 (en) 1999-02-16 2013-11-05 Novartis Ag Spontaneously dispersible N-benzoyl staurosporine compositions
CZ303979B6 (cs) * 1999-02-16 2013-07-31 Novartis Ag Spontánne dispergovatelná farmaceutická kompozice N-benzoylstaurosporinu
WO2000048571A1 (en) * 1999-02-16 2000-08-24 Novartis Ag Spontaneously dispersible n-benzoyl staurosporine compositions
WO2000062781A1 (de) * 1999-04-20 2000-10-26 Florian Lang Arzneimittel enthaltend hemmstoffe der zellvolumenregulierten humanen kinase h-sgk
WO2002017893A3 (de) * 2000-08-28 2003-01-23 Florian Lang Sgk2 und sgk3 als diagnostische und therapeutische targets
WO2002017893A2 (de) * 2000-08-28 2002-03-07 Florian Lang Sgk2 und sgk3 als diagnostische und therapeutische targets
AU2003215623B2 (en) * 2003-03-03 2009-10-22 Florian Lang Sgk1 as diagnostic and therapeutic target
WO2004079003A1 (de) * 2003-03-03 2004-09-16 Florian Lang Sgk1 als diagnostisches und therapeutisches target
WO2004108132A1 (en) * 2003-06-06 2004-12-16 Novartis Ag Staurosporine derivatives for hypereosinophilic syndrome
EP2305265A1 (de) 2003-08-08 2011-04-06 Novartis AG Kombinationen mit Staurosporinen
WO2006082448A1 (en) * 2005-02-07 2006-08-10 Topotarget Uk Limited Assays for agents with selective cytotoxicty to hdac resistant cell lines

Also Published As

Publication number Publication date
PT657164E (pt) 2000-04-28
EP0657164B1 (de) 1999-10-27
DE69421366T2 (de) 2000-03-23
IL111872A (en) 1998-02-08
AU692801B2 (en) 1998-06-18
KR960021018A (ko) 1996-07-18
CA2137764A1 (en) 1995-06-12
AU8030894A (en) 1995-06-22
ES2140512T3 (es) 2000-03-01
KR100366176B1 (ko) 2003-03-03
JPH07196512A (ja) 1995-08-01
DK0657164T3 (da) 2000-04-17
CA2137764C (en) 2006-02-07
NZ270109A (en) 1996-11-26
GR3032368T3 (en) 2000-04-27
ZA949824B (en) 1995-07-13
GB9325395D0 (en) 1994-02-16
ATE185970T1 (de) 1999-11-15
US5736542A (en) 1998-04-07
DE69421366D1 (de) 1999-12-02
PH31454A (en) 1998-11-03
IL111872A0 (en) 1995-06-29

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